Project Summary The ultimate goal of this research is to define the mechanisms through which specific endocrine and genetic risk factors contribute to breast cancer development. The focus of this proposed study is Emca4, a genetic determinant of susceptibility to 17?-estradiol (E2)-induced mammary cancer in the rat that has been mapped to rat chromosome 7 (RNO7). Data presented herein indicate that Emca4 harbors multiple genetic determinants of mammary cancer susceptibility that are orthologous to breast cancer risk loci mapped to chromosome 8q24.21. Also presented are novel data that indicate that a risk prediction model based on genotype across the Emca4 orthologous regions in the human genome can accurately distinguish cases from controls in a previously characterized case/control cohort. The primary objectives of this proposed study are to identify the cell types in which and the mechanisms through which the Emca4 variants influence development of mammary cancer. The knowledge gained will be translate to studies of human derived biospecimens to assess relevance of the data emerging from the rat models. Aim 1 is to define the mechanisms through which Emca4.1 determines susceptibility to E2-induced mammary cancer. The genes upon which the Emca4.1 variants act will be identified in defined mammary cell populations. Aim 2 is to define the mechanism through which Emca4.4 influences mammary cancer susceptibility and modifies the actions of Emca4.1. The molecular bases of the epistatic interactions between Emca4.4 and Emca4.1 on mammary cancer susceptibility and the cellular and molecular phenotypes regulated by Emca4.4 and Emca4.1 will be defined. Specific Aim 3 is to define the function(s) of Pvt1 in the rat mammary gland and its role in mammary cancer development. Attention will be focused on functionally characterizing Pvt1 promoters and exons that are impacted by endocrine and genetic factors or differ between matched normal and neoplastic mammary/breast tissues. Novel, physiologically relevant, rat models of E2-induced mammary cancer will be utilized in this research. Successful completion of the proposed studies proposed is expected to identify the cell types in which the actions of the Emca4 variants on mammary cancer susceptibility are exerted, the specific gene product(s) that confers the actions of the Emca4 variants in those cell types, and the downstream biological processes that are influenced by the functional orthologs that reside within Emca4. The information generated in these studies is expected to advance our understanding of the etiology of the luminal breast cancer subtypes.